Endometriosis Sun-Wei Guo Shanghai OB/GYN Hospital Fudan University Shanghai College of Medicine

Learning objectives To know Definition of endometriosis Its signs and symptoms Some notable features of endometriosis Its diagnosis Epidemiology Its treatedment

Definition of endometriosis “endo”: inside E.g. endoscopy, endocrinology, “metra”: womb, uterus A gynecological condition in which endometrial cells appear and grow outside the uterine cavity Endometrial cells: Both stromal and epithelial cells If appeared in the myometrium, it’s called adenomyosis (once called “endometriosis in interna”) Lesions: ectopic endometrium, endometriotic lesion, (ectopic) endometrial implant

Signs and Symptoms Recurring pelvic pain (rarely, pain in other body parts) Chronic pelvic pain Dysmenorrhea (painful menstruation) Dyspareunia (painful sex) Dysuria (painful voiding) Infertility Menstrual disturbances

Some notable characteristics Estrogen-dependence Invasiveness Like tumors, endometriotic cells are invasive Adhesion Tough to treat, let alone cure Quite common ~ ¼ gynecological surgeries are endometriosis-related A debilitating disease Loss of productivity Reduction in life quality Emotional and relationtional burden Quite expensive to treat $2800/yr for Tx, then $1000/yr for loss of productivity In China, ~15000 Yuan for surgery+medication+hospitalization

Epidemiology: prevalence Incidence Unknown Mostly women of reproductive age Prevalence 1-22%, depending on screening method and the population; precise number unknown Often 10% is used ~26.1% in women with infertility 17.7% in women with pelvic pain 5.7% in women undergoing sterilization

Epidemiology: risk factors Consistently identified (“incessant menstruation”) Earlier age of menarche Shorter menstrual cycle Lower parity Controversial Dioxin exposure Heavier menses Alcohol consumption Red hair Protective factors Regular exercise Smoking

Subtypes of endometriosis Depending mostly on location Ovarian endometriosis (ovarian endometriomas) Unilateral or bilateral Mostly < 5 cm in size Peritoneal endometriosis Deep infiltrating endometriosis (DIE) Rectovaginal Ovarian endometriomas is the most common (40-80%, depending on hospital)

Extraperitoneal endometriosis Lung, brain, nose, eyelid,… Very rarely, in men with prostate cancer after receiving estrogen therapy

Pathogenesis Formal description by Von Rokitansky (1860) Largely unknown (“An enigma”) Many theories, yet none proven Retrograde menstruation Coelomic metaplasia (peritoneum and endometrium are both derived from the coelomic cells) Müllerianosis Neoclassic theories Dioxin exposure Prenatal exposure Genetic predisposition Immune deficiency

Laparoscopic photographs Ovarian endometrioma: chocolate cyst Ovarian endometrioma: “kissing ovaries” Peritoneal endometriosis

The most popular theory John A. Sampson’s retrograde menstruation theory Viable menstrual debris is regurgitated into the pelvic cavity through the fallopian tubes, attatches itself to ectopic sites, invades the tissue and grows Evidence Human experimentation (innoculation of menstrual debris did cause endometriosis) Uterine dysperistalsis and hyperperistalsis in endometriosis Animal experiment (in baboons) Anatomic anomaly (closure of cervical os and endometriosis) Yet retrograde menstruation occurs in >95% of women with patent fallopian tubes; why not all of them develop endometriosis?

Diagnosis Gold standard: Imaging: Signs and symptoms Direct visualizationof endometriotic lesions usu. by laparoscopy or laparotomy Imaging: Ultrasonography MRI CT Signs and symptoms Secondary dysmenorrhea Dyspareunia Infertility Gynecological examination Histological confirmation The presence of both endometrial stroma and epithelium Blood biochemistry

Laparoscopy/laparotomy Pros: “Gold standard” Can also remove lesions Cons Invasive procedure Has its own risk of morbility and, rarely, mortality Costly Still difficult to detect microscopic and/or subperitoneal lesions Accuracy depends on the skill levels of surgeons

Staging of endometriosis The revised American Fertility Society (rAFS) scoring system is the most widely used (1995) Could be used for determining treatment modalities A score is assigned to lesions based on Location Number of lesions Size Infiltration depth Presence of adhesion 0—140 rAFS stage: I: 1-5 II: 6-15 III: 16-40 IV: >40 Problems It does not correlate with either the severity of pain or infertility It has no predictive value in prognosis

Serum markers Over 200 different serum biomarkers have been proposed, yet none stands the test of time The most used: CA125 > 30 U/ml CA125 level can be elevated in moderate/severe cases Pros Non-invasive Cheap Fast Cons Low sensitivity/specificity

Symptomology Pains Infertility Secondary dysmenorrhea Dyspareunia Progressive Infertility Other factors ruled out Difficulty in conceiving Problems in implantation Cyclic pains/bleedings (or bloody cough) Caution: the signs and symptoms are not specific

Gynecological examination Pelvic exam Appearance (for cutaneous lesions) Test for uterus size Palpation of any nodules or tenderness on or near the posterior wall of the uterus (Douglas pouch, cul de sac) Palpation of adnexal mass Limited value

Radiologic imaging CT Pros Cons MRI Non-invasive Cheaper than surgery Lacks sufficient sensitivity and specificity Somewhat expensive Lower availability MRI Performed after day 8 of the cycle Anti-peristaltic i.m. T1 or T2-weighted images, before/after taking contrast Good for peritoneal and ovarian endometriosis CT Only good for endometriosis in the lung

Ultrasound Excellent for ovarian endometriomas “Chocolate cyst” is filled with old blood, giving a typical ground-glass appearance with low-level echoes Not good for other types of endometriosis

Differential diagnosis Ovarian malignancy Adenomyosis Pelvic Inflammatory Disease (PID)

Treatment goals To alleviate pains To delay recurrence as long as possible To help patients get pregnant

Treatment options Thoughts before deciding the treatment Symptoms Pain or infertility or both Patient characteristics Age Severity of disease Severity of pain Prior treatment history Reproductive needs Other wishes

Some rough guidelines First-line medical treatment: patients with mild symptoms or adolascent girls Medical treatment: Patients with endometriosis who wish to get pregnant Fertility-preserving surgery: Young patients with severe endometriosis who wishes to have children Ovary-preserving surgery+medication: young patients with severe endometriosis who does not wish to have children Radical surgery: Older patients with severe endometriosis who do not wish to have children

Treatment options Surgery Non-surgical treatment (medication) Laparoscopy or laparotomy Radical or conservative Non-surgical treatment (medication) First-line medication Progestins Gonadotropin-releasing hormone (GnRH) agonists Danazol (androgenic) Oral contraceptives Controlled ovarian hyperstimulation (fertility treatment)

Surgery Indications Purposes Medical treatment ineffective Size of the adnexal mass > 5 cm Wishing to get pregnant Purposes Accurate diagnosis Removal of endometriotic lesions as much as possible Removal of adhesion and restoration of normal anatomy

Surgery: Pros and cons Pros Cons Proven efficacy Invasive Costly Certain risks Due to high recurrence risk (~50% 5 yrs), 2nd surgery may be needed Increases the risk of damaging ovaries, and the risk of premature ovarian failure

Medical treatment: Expectant treatment Use NSAIDs Asprin Other analgesics such as ibuproten Selective COX-2 inhibitors Little impact, if any, on endometriotic lesions Follow-up

Medical treatment Principles (for current treatment modalities) To suppress ovarian estrogen production (GnRH-a and danazol) necessary for the development and maintenance of ectopic endometrium To induce a pseudo-pregnency (progestins and OC), which suppresses ovulation and estrogen production With reduced estrogen production, endometriotic lesions may shrink in size or may be eliminated All are short-term; recurrence after termination All have various side-effects ~10% simply do not respond to pregestin therapy

Progestin treatment Based on a serendipitous finding that pregnancy relieves the sysmptoms of endometriosis Mechanism of action (MOA) Suppresses ovulation Suppress the growth of endometriotic lesions Reduce inflammation Progestins Oral Norethisterone acetate Cyproterone acetate Dienogest Intramuscular route Medroxiprogesterone acetate Intrauterine route Levonorgestrel-releasing IUD Side-effects Spotting, hot-flashes, breakthrough bleeding

GnRH agonists treatment MOA Negative feedback control of ovarian estrogen production Method of administration Injection Side-effects Hot-flashes loss of libido vaginal dryness, decreased bone density Quite expensive

Danazol treatment MOA Danazol is a modified androgen 2.5-3.5% of activity of methyl testosterone MOA Antagonizes estrogen at the tissue level Blocks estrogen receptor sites Suppresses ovulation (and thus estrogen production) Alters pulsatile GnRH release patterns Side-effects: weight gain, acne, hirsutism, … Decreased use after GnRHa introduction

Treatment with oral contractives MOA Suppresses ovulation Induces a psudopregnancy state Not approved by the USFDA yet Often used as an “empirical” treatment (w/o a firm Dx) Pros Low cost Easy Addition to contraception Cons Not good for women who wish to get pregnant

Other medical treatment Traditional Chinese medicine A recent review indicates that evidence is not there due to poor quality Mifepristone (RU486) Inadequate evidence

Treatment on the horizon GnRH antagonists Removes the “flare-up” More precise control

Take home messages Endometriosis is a very complex disease It involves hormones, immunology, neuroscience, molecular biology, genetics, epigenetics, and clinical research Pathogenesis largely unknown Treatment not very satisfactory Can be an exciting research area

“He who knows endometriosis knows gynecology”